The Human Fungal Pathogen Cryptococcus neoformans Escapes Macrophages by a Phagosome Emptying Mechanism That Is Inhibited by Arp2/3 Complex-Mediated Actin Polymerisation

The lysis of infected cells by disease-causing microorganisms is an efficient but risky strategy for disseminated infection, as it exposes the pathogen to the full repertoire of the host's immune system. Cryptococcus neoformans is a widespread fungal pathogen that causes a fatal meningitis in HIV and other immunocompromised patients. Following intracellular growth, cryptococci are able to escape their host cells by a non-lytic expulsive mechanism that may contribute to the invasion of the central nervous system. Non-lytic escape is also exhibited by some bacterial pathogens and is likely to facilitate long-term avoidance of the host immune system during latency. Here we show that phagosomes containing intracellular cryptococci undergo repeated cycles of actin polymerisation. These actin ‘flashes’ occur in both murine and human macrophages and are dependent on classical WASP-Arp2/3 complex mediated actin filament nucleation. Three dimensional confocal imaging time lapse revealed that such flashes are highly dynamic actin cages that form around the phagosome. Using fluorescent dextran as a phagosome membrane integrity probe, we find that the non-lytic expulsion of Cryptococcus occurs through fusion of the phagosome and plasma membranes and that, prior to expulsion, 95% of phagosomes become permeabilised, an event that is immediately followed by an actin flash. By using pharmacological agents to modulate both actin dynamics and upstream signalling events, we show that flash occurrence is inversely related to cryptococcal expulsion, suggesting that flashes may act to temporarily inhibit expulsion from infected phagocytes. In conclusion, our data reveal the existence of a novel actin-dependent process on phagosomes containing cryptococci that acts as a potential block to expulsion of Cryptococcus and may have significant implications for the dissemination of, and CNS invasion by, this organism.\ud \u

Signatures of Majorana fermions in hybrid superconductor-semiconductor nanowire devices

Majorana fermions are particles identical to their own antiparticles. They have been theoretically predicted to exist in topological superconductors. We report electrical measurements on InSb nanowires contacted with one normal (Au) and one superconducting electrode (NbTiN). Gate voltages vary electron density and define a tunnel barrier between normal and superconducting contacts. In the presence of magnetic fields of order 100 mT we observe bound, mid-gap states at zero bias voltage. These bound states remain fixed to zero bias even when magnetic fields and gate voltages are changed over considerable ranges. Our observations support the hypothesis of Majorana fermions in nanowires coupled to superconductors.Comment: Raw data available at http://dx.doi.org/10.4121/uuid:8bf81177-2f2b-49c2-aaf5-d36739873dd

An exploration of socio-economic and food characteristics of high trans fatty acid consumers in the Dutch and UK national surveys after voluntary product reformulation

Trans fatty acids (TFA) increase the risk of mortality and chronic diseases. TFA intakes have fallen since reformulation, but may still be high in certain, vulnerable, groups. This paper investigates socio-economic and food consumption characteristics of high TFA consumers after voluntary reformulation in the Netherlands and UK. Post-reformulation data of adults aged 19–64 was analysed in two national surveys: the Dutch National Food Consumption Survey (DNFCS) collected 2007–2010 using 2*24hr recalls (N = 1933) and the UK National Diet and Nutrition Survey (NDNS) years 3&4 collected 2010/11 and 2011/12 using 4-day food diaries (N = 848). The socio-economic and food consumption characteristics of the top 10% and remaining 90% TFA consumers were compared. Means of continuous data were compared using t-tests and categorical data means using chi-squared tests. Multivariate logistic regression models indicated which socio-demographic variables were associated with high TFA consumption. In the Dutch analyses, women and those born outside the Netherlands were more likely to be top 10% TFA consumers than men and Dutch-born. In the UK unadjusted analyses there was no significant trend in socio-economic characteristics between high and lower TFA consumers, but there were regional differences in the multivariate logistic regression analyses. In the Netherlands, high TFA consumers were more likely to be consumers of cakes, buns & pastries; cream; and fried potato than the remaining 90%. Whereas in the UK, high TFA consumers were more likely to be consumers of lamb; cheese; and dairy desserts and lower crisps and savoury snack consumers. Some socio-demographic differences between high and lower TFA consumers were evident post-reformulation. High TFA consumers in the Dutch 2007–10 survey appeared more likely to obtain TFA from artificial sources than those in the UK survey. Further analyses using more up-to-date food composition databases may be needed

Dairy consumption and cardiometabolic diseases: systematic review and updated meta-analyses of prospective cohort studies

Purpose of Review Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by reviewing the literature and updating meta-analyses of observational studies. Recent Findings We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with a 3–4% lower risk of diabetes. Yogurt was non-linearly inversely associatedwith diabetes (RR = 0.86, 95%CI: 0.83–0.90 at 80 g/ d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with an 8% lower risk of stroke. Summary The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic diseases

Study of intrinsic risk factors for falls in institutionalized elderly people

Esta pesquisa teve como objetivo identificar a presença de fatores intrínsecos que predispõem a quedas em idosos moradores em instituições de longa permanência na cidade de Goiânia (GO). Trata-se de estudo descritivo transversal realizado em seis instituições de longa permanência para idosos existentes na cidade de Goiânia. A amostra da investigação constou de 95 idosos que atenderam aos critérios de inclusão e exclusão. Utilizou-se um questionário contendo dados clínicos relacionados às condições de saúde-doença; dados cognitivos; avaliação da capacidade para as atividades básicas de vida diária e avaliação do equilíbrio e marcha. Os idosos avaliados, no geral, apresentam vários fatores de risco, apontados pela literatura, para quedas, tais como: relato de dificuldade motora em membros inferiores (90%), déficit visual (81,1%), uso de três ou mais medicamentos (59,7%), suspeita de depressão (37,9%), falta de equilíbrio em apoio unipodal (37,9%) e altura do passo anormalmente diminuída (32,6%). As informações obtidas nos permitem apontar condições determinantes que aumentam a possibilidade dos eventos queda acontecerem na amostra estudada, sinalizando à necessidade de que estratégias de promoção de saúde, prevenção de agravos e reabilitação devam ser tomadas. _________________________________________________________________________________________ ABSTRACTThe objective of this research was to identify intrinsic risk factors that predispose elderly people living in long-term institutions in the city of Goiânia (GO) to falls. The present descriptive transversal study was carried out in six long-term institutions for seniors in the city of Goiânia. The investigated sample consisted of 95 elderly that fitted the inclusion and exclusion criteria. A questionnaire was used for collecting clinical data related to health-disease conditions; cognitive data; capacity to develop basic daily life activities and equilibrium and gait. In general terms, as pointed out the literature, the examined elderly presented different fall risk factors such as: motor difficulty in lower limbs (90%), visual deficit (81,1%), use of 3 or more kinds of medicines (59,7%), suspected depression (37,9%), lack of equilibrium/unstable unipodal support (37,9%) abnormally decreased height in step (32,6%). The obtained data allow us to set indicators for the increase in falls among the studied sample, demonstrating the need for creating strategies for health promotion, prevention of injuries and rehabilitation

The way that you do it? An elaborate test of procedural invariance of TTO, using a choice-based design

The time tradeoff (TTO) method is often used to derive Quality-Adjusted Life Year health state valuations. An important problem with this method is that results have been found to be responsive to the procedure used to elicit preferences. In particular, fixing the duration in the health state to be valued and inferring the duration in full health that renders an individual indifferent, causes valuations to be higher than when the duration in full health is fixed and the duration in the health state to be valued is elicited. This paper presents a new test of procedural invariance for a broad range of time horizons, while using a choice-based design and adjusting for discounting. As one of the known problems with the conventional procedure is the violation of constant proportional tradeoffs (CPTO), we also investigate CPTO for the alternative TTO procedure. Our findings concerning procedural invariance are rather supportive for the TTO procedure. We find no violations of procedural invariance except for the shortest gauge duration. The results for CPTO are more troublesome: TTO scores depend on gauge duration, reinforcing the evidence reported when using the conventional procedure

Shot noise in mesoscopic systems

This is a review of shot noise, the time-dependent fluctuations in the electrical current due to the discreteness of the electron charge, in small conductors. The shot-noise power can be smaller than that of a Poisson process as a result of correlations in the electron transmission imposed by the Pauli principle. This suppression takes on simple universal values in a symmetric double-barrier junction (suppression factor 1/2), a disordered metal (factor 1/3), and a chaotic cavity (factor 1/4). Loss of phase coherence has no effect on this shot-noise suppression, while thermalization of the electrons due to electron-electron scattering increases the shot noise slightly. Sub-Poissonian shot noise has been observed experimentally. So far unobserved phenomena involve the interplay of shot noise with the Aharonov-Bohm effect, Andreev reflection, and the fractional quantum Hall effect.Comment: 37 pages, Latex, 10 figures (eps). To be published in "Mesoscopic Electron Transport," edited by L. P. Kouwenhoven, G. Schoen, and L. L. Sohn, NATO ASI Series E (Kluwer Academic Publishing, Dordrecht

Combining Path Integration and Remembered Landmarks When Navigating without Vision

This study investigated the interaction between remembered landmark and path integration strategies for estimating current location when walking in an environment without vision. We asked whether observers navigating without vision only rely on path integration information to judge their location, or whether remembered landmarks also influence judgments. Participants estimated their location in a hallway after viewing a target (remembered landmark cue) and then walking blindfolded to the same or a conflicting location (path integration cue). We found that participants averaged remembered landmark and path integration information when they judged that both sources provided congruent information about location, which resulted in more precise estimates compared to estimates made with only path integration. In conclusion, humans integrate remembered landmarks and path integration in a gated fashion, dependent on the congruency of the information. Humans can flexibly combine information about remembered landmarks with path integration cues while navigating without visual information.National Institutes of Health (U.S.) (Grant T32 HD007151)National Institutes of Health (U.S.) (Grant T32 EY07133)National Institutes of Health (U.S.) (Grant F32EY019622)National Institutes of Health (U.S.) (Grant EY02857)National Institutes of Health (U.S.) (Grant EY017835-01)National Institutes of Health (U.S.) (Grant EY015616-03)United States. Department of Education (H133A011903

Treatment of Cryptococcal Meningitis in KwaZulu-Natal, South Africa

BACKGROUND: Cryptococcal meningitis (CM) remains a leading cause of death for HIV-infected individuals in sub-Saharan Africa. Improved treatment strategies are needed if individuals are to benefit from the increasing availability of antiretroviral therapy. We investigated the factors associated with mortality in routine care in KwaZulu-Natal, South Africa. METHODOLOGY/PRINCIPAL FINDINGS: A prospective year long, single-center, consecutive case series of individuals diagnosed with cryptococcal meningitis 190 patients were diagnosed with culture positive cryptococcal meningitis, of whom 186 were included in the study. 52/186 (28.0%) patients died within 14 days of diagnosis and 60/186 (32.3%) had died by day 28. In multivariable cox regression analysis, focal neurology (aHR 11 95%C.I. 3.08-39.3, P<0.001), diastolic blood pressure<60 mmHg (aHR 2.37 95%C.I. 1.11-5.04, P=0.025), concurrent treatment for tuberculosis (aHR 2.11 95%C.I. 1.02-4.35, P=0.044) and use of fluconazole monotherapy (aHR 3.69 95% C.I. 1.74-7.85, P<0.001) were associated with increased mortality at 14 and 28 days. CONCLUSIONS: Even in a setting where amphotericin B is available, mortality from cryptococcal meningitis in this setting is high, particularly in the immediate period after diagnosis. This highlights the still unmet need not only for earlier diagnosis of HIV and timely access to treatment of opportunistic infections, but for better treatment strategies of cryptococcal meningitis